Grant: Project Grant

Pulmonary arterial hypertension (PAH) is a progressive and lethal condition that affects the smallest arteries of the lung. It is thought to be triggered by damage to the inner lining of blood vessels, the endothelial cells, leading to narrowing and blockage of small lung arteries. This makes it harder for the blood to flow through the lungs and therefore results in an increase in pulmonary arterial pressure. We have established an animal model of PAH that closely resembles the human disease. In this model we have shown that the initial endothelial cell injury resulted in a loss of nearly 80% of small lung arteries. This occurred very early on in the disease such that the remaining arteries had to accommodate all lung blood flow, which resulted in harmful stress on the inner lining cells. This stress perpetuated endothelial injury, ultimately overwhelming the blood vessels' ability to repair the damage, whereas reducing this damaging blood flow prevented and reversed lung arterial loss and remodeling in this model. In this proposal we will use a new technology that allows us to assess the activity of all genes within individual cells of the lung. In this way we can identify novel cell populations that are involved in either the repair of the lung arterial injury or in the abnormal remodeling of blood vessels that leads to their blockage. We have already identified several new endothelial cell populations; for example, an endothelial stem cell population that may be important in blood vessel repair but appears to be compromised in this model. As well, we have identified a novel 'activated' endothelial population that may be involved in abnormal cell growth and blockage of small lung arteries, as well as in promoting blood vessel inflammation that is a well-known feature of this disease. We expect that these new insights will lead to novel and potentially curative treatment strategies, which will be explored in the animal models of PAH.